Population Genetics of Mobile Elements

描述（由申请人提供）：包括Alu和LINE1 （LI）元件在内的分散重复元件占人类基因组的45%，但其起源和动态尚不清楚。有证据表明，这些因素影响基因多样性在基因组中的分布，因为它们对重组等过程有影响。该项目的目标是建立在从上一个资助期获得的知识基础上，以追求有关Alu和LI元素的起源及其对基因组多样性模式的影响的问题。通过一系列的PCR和测序实验，我们将评估基因转换对Alu多样性的影响。我们将评估50个基因组区域的连锁不平衡模式，以验证Alu元件介导同源重组的假设。我们将对人类和黑猩猩的基因组进行比较，以验证Alu元素是不平等交叉事件、基因删除和复制的重要媒介的假设。我们预测，由于LI元素在基因组中的分布和密度较低，它们作为不平等交叉媒介的频率较低。我们设计了一系列实验来验证Alu元件以不依赖于内切酶的方式插入基因组的假设，因此可能参与双链DNA断裂的修复。最后，我们将应用新开发的方法来确定自然选择是否对人类基因组中的Alu和LI元素起作用。

DESCRIPTION (provided by applicant): Interspersed repetitive elements, including Alu and LINE1 (LI) elements, make up 45% of the human genome, yet much remains unknown about their origins and dynamics. There is evidence that these elements affect the distribution of genetic diversity across the genome because of their influence on processes like recombination. The goals of this project are to build upon the knowledge gained from the previous funding period in order to pursue questions about the origins of Alu and LI elements and about their effects on patterns of genomic diversity. Using a series of PCR and sequencing experiments, we will evaluate the effects of gene conversion on Alu diversity. We will assess linkage disequilibrium patterns in 50 genomic regions to test the hypothesis that Alu elements mediate homologous recombination. We will undertake comparisons of human and chimpanzee genomes to test the hypothesis that Alu elements are important mediators of unequal crossover events, deleting and duplicating genes. We predict that LI elements, because of their observed distribution and their lower density in the genome, function less frequently as mediators of unequal crossover. We have designed a series of experiments to test the hypothesis that Alu elements insert into the genome in an endonuclease-independent fashion and may therefore participate in the repair of double-stranded DNA breaks. Finally, we will apply newly developed methods to determine whether natural selection has been operating on Alu and LI elements in the human genome. Factors like gene conversion and recombination exert important effects on patterns of genomic diversity, which in turn influence patterns of linkage disequilibrium in the genome. The proposed research, which will help to explore the influence of repetitive elements on genomic diversity, will thus have important implications for the use of linkage disequilibrium in localizing disease-causing genes. Our understanding of genetic disease will also be enhanced by a better understanding of the role of these elements in DNA repair and in gene duplication and deletion.